HER2-RADiCAL

The HER2-RADiCAL study is for patients with HER2-positive breast cancer who: -started their course of drug treatment (chemotherapy + trastuzumab + pertuzumab) before surgery; -have had breast surgery; -and have been found to have the best possible response to treatment (a “pathological complete response” or “pCR”). A pCR means that there were no remaining living cancer cells in tissue removed at surgery. We already know that such patients have good outcomes with only a small chance of the cancer returning, and so it is possible that the side effects and risks of continuing all of these treatments in combination could outweigh any benefit. The study will investigate whether a more personalised treatment plan can be offered, with the aim of allowing patients with a pCR to safely receive less drug treatment after surgery. Study participants will continue treatment with trastuzumab to complete 9 cycles (rather than 18), including the cycles given before surgery. No more pertuzumab or any type of chemotherapy will be given after surgery. Some patients may avoid receiving a type of drug called an anthracycline (where the anthracycline-containing chemotherapy component is deferred after surgery). Any other treatment that might have been recommended (like hormone therapy or radiotherapy) will be given as normal. Patients will be asked to donate tissue samples removed during routine biopsy procedures or surgery. No new tissue samples will be taken for research purposes. The HER2-RADiCAL study aims to recruit around 720 patients with HER2-positive breast cancer and a pCR, to test whether these patients can safely receive less trastuzumab, pertuzumab and chemotherapy after surgery. This reduction of drug treatment may not only benefit the patient, but also save NHS resources. Data from routine NHS records on all patients with HER2-positive breast cancer in the UK will be collected in addition to the study data to assess the cost-effectiveness of this response-adapted approach 

1. Female or male, age ≥ 16

2. Histologically confirmed invasive breast cancer that is HER2-positive (IHC3+, and/or ISH positive/amplified) as determined by the local laboratory in accordance with national guidelines

3. Has received neoSACT chemotherapy with concomitant trastuzumab and pertuzumab

4. pCR (ypT0/is ypN0) in breast and sampled regional lymph nodes as per local pathology reporting

5. Imaging of breast and axilla prior to initiation of neoSACT and either:

a) Breast primary radiological measurement ≤ 20mm prior to neoSACT and limited nodal involvement (cN1) confirmed by axillary core biopsy or FNA (cT1N1)

OR

b) Breast primary radiological measurement >20mm but ≤ 50mm and node-negative (cT2N0) or limited nodal involvement (cT2N1)

6. Multiple ipsilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria

7. Bilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria

8. Pre-treatment diagnostic breast tumour biopsy sample available

9. Patient must be fit to continue treatment with trastuzumab and have no concomitant medical, psychiatric or social problems that might interfere with informed consent, adherence to the reduced treatment pathway or follow up

10. Provision of written informed consent to participate in HER2-RADiCAL 

1. Evidence of metastatic disease at any time since diagnosis 

2. Any residual invasive disease following neoSACT. This includes isolated tumour cells in axillary nodes or tissue or evidence of lymphovascular invasion in the breast. Persistent ductal or lobular non-invasive disease (DCIS or LCIS) is permitted. Resection margins must be deemed clear of any residual DCIS according to local MDT protocol.

3. Breast conserving primary surgery where it is known that breast irradiation will not be administered (e.g. due to contraindication or patient preference)

4. Intraoperative assessment of post-neoSACT axillary SLN using one stop nucleic acid amplification (OSNA)

5. Any planned further resectional surgery for breast cancer (including re-excision, mastectomy, or axillary surgery excluding reconstructive or risk reducing surgery)

6. HER2-negative invasive breast carcinoma

7. Breast cancer with clinical stage of T≥3 at diagnosis

8. Evidence of scarring (or other pathological features consistent with previous malignant involvement) in ≥4 axillary nodes or clinical nodal stage N≥2 at any time

9. Positive SLNB pre-neoadjuvant systemic therapy as this precludes determination of pCR

10. Pregnant and/or lactating women

11. Female patient of child-bearing potential, unwilling to use an effective form of contraception during trastuzumab treatment and for 7 months after their last dose of trastuzumab (NB. See section 5.5 for further guidance) 

12. Previous diagnosis of invasive breast carcinoma

13. Previous diagnosis of any other (non-breast) malignancy unless disease-free for at least 5 years and considered to be at low risk of recurrence or treated basal cell or localised squamous cell carcinoma of the skin or cervical intraepithelial neoplasia

14. Chemotherapy administered following surgery (NB. Pertuzumab and/or trastuzumab may have been continued after surgery as per local practice prior to trial entry)

15. Has received >9 cycles trastuzumab. In the event a patient has received 9 cycles prior to study entry then consent must occur within 3 weeks of last dose of trastuzumab.  

16. Clinically significant cardiac disease within 12 months of starting trastuzumab, including unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, cerebral vascular accident, or cardiac arrhythmia associated with haemodynamic instability

17. Left ventricular ejection fraction (LVEF) less than 50% on most recent cardiac imaging

18. History of interstitial lung disease

19. Any medical or other contra-indication to continuing trastuzumab 

Research Nurse: Louisa Campy (Louisa.Campy@elht.nhs.uk)

Administrator: Oncology Research Team